A primary constraint on pharmaceutical development is the poor coverage of chemical space. This lack of molecular diversity and breadth has been largely dictated by synthetic expediency. More complex compounds, which may offer increased potency or selectivity, become intractable for therapeutic development because of the daunting synthetic challenge. The overall objective of this application is to design and execute efficient synthetic routes to a host of natural products featuring an impressive array of biological properties. This objective is driven by the innovation of new transformations based on alkyne activation. The proposal outlines three specific aims to be pursued in parallel. Each aim is focused on the total synthesis of one or more bioactive natural product, where a key transformation will be developed that will rapidly establish the complex molecular architecture embedded within the target(s). Aim 1 delineates an efficient route to alotaketal A, a molecule implicated in cAMP signaling, holding potential for the treatment of cancer and neurodegenerative disease. This plan relies on the application of a silicon group migration to construct the tricyclic core. Aim 2 describes novel approaches to both liphagal, a PI3K ? inhibitor, and xiamycin A, an antibacterial agent. Both routes to these targets feature a metal-catalyzed polycyclization event to establish their complex ring systems. Lastly, Aim 3 outlines a unified synthetic strategy toward the Gelsemium alkaloids. Several of these compound have intriguing bioactivity (including anti-A431 human epidermoid carcinoma), and their dense architectures represent significant challenges in synthesis. Here, the pivotal tandem transformation to access the core involves the formation of two C-C bonds and multiple stereocenters from a single, readily accessed stereogenic carbon. Unifying these aims is the application of alkyne activation in novel chemical transformations. The emphasis of these reactions is on the efficient construction of molecular complexity, envisioned in the form of multiple bond-forming events and selective generation of stereogenic carbon centers. Our synthetic approaches to these complex natural products provide an excellent construct for the invention of these transformations. Moreover, the biological relevance of the targeted molecules highlights the potential impact of our reaction development in medicinal contexts. We expect our studies will have measurable implications in future therapeutic development, both in the targets we specifically pursue and in the widely applicable methods that are established.